Mugo Jacquiline W, Day Cascia, Choudhury Ananyo, Deetlefs Maria, Freercks Robert, Geraty Sian, Panieri Angelica, Cotchbos Christian, Ribeiro Melissa, Engelbrecht Adelein, Ramsay Michèle, Sarah Pedretti, Peter Jonny
Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town, 7625, Western Cape, South Africa.
Allergy and Immunology Unit, University of Cape Town Lung Institute (Pty) Ltd, George Street, Mowbray, Cape Town, 7700, Western Cape, South Africa.
medRxiv. 2024 Sep 15:2024.09.13.24313664. doi: 10.1101/2024.09.13.24313664.
Angiotensin-converting enzyme inhibitor-induced angioedema (AE-ACEI) is a life-threatening adverse event and, globally, the commonest cause of emergency presentations with angioedema. Several large genome-wide association studies (GWAS) have found genomic associations with AE-ACEI. However, despite African Americans having a 5-fold increased risk of AE-ACEI, there are no published GWAS from Africa. The aim of this study was to conduct a case-control GWAS of AE-ACEI in a South African population and perform a meta-analysis with an African American and European American population.
The GWAS included 202 South African adults with a history of AE-ACEI and 513 controls without angioedema following angiotensin-converting enzyme inhibitor (ACEI) treatment for at least 2 years. A meta-analysis was conducted with GWAS summary statistics from an African American and European American cohort (from Vanderbilt/Marshfield with 174 cases and 489 controls).
No SNPs attained genome-wide significance. However, 26 SNPs in the post-imputation standard GWAS of the South African cohort and 37 SNPs in the meta-analysis were associated to AE-ACEI with suggestive threshold(p-value<5.0×10). Some of these SNPs were found to be located close to the genes and previously linked with drug-induced angioedema, and also close to the gene linked to ACEI cough, providing replication at the gene level, but with novel lead SNPs.
Our results highlight the importance of African populations to detect novel variants in replication studies. Further increased sampling across the continent and matched functional work are needed to confirm the importance of genetic variation in understanding the biology of AE-ACEI.
血管紧张素转换酶抑制剂诱发的血管性水肿（AE-ACEI）是一种危及生命的不良事件，在全球范围内，是血管性水肿急诊就诊最常见的原因。多项大型全基因组关联研究（GWAS）已发现与AE-ACEI相关的基因组关联。然而，尽管非裔美国人发生AE-ACEI的风险增加了5倍，但非洲尚未发表GWAS研究。本研究的目的是在南非人群中开展AE-ACEI的病例对照GWAS研究，并与非裔美国人和欧洲裔美国人进行荟萃分析。
该GWAS研究纳入了202名有AE-ACEI病史的南非成年人以及513名在接受血管紧张素转换酶抑制剂（ACEI）治疗至少2年后未发生血管性水肿的对照者。利用来自非裔美国人和欧洲裔美国人队列（范德比尔特/马什菲尔德，174例病例和489名对照）的GWAS汇总统计数据进行荟萃分析。
没有单核苷酸多态性（SNP）达到全基因组显著性。然而，南非队列的插补后标准GWAS中有26个SNP，荟萃分析中有37个SNP与AE-ACEI相关，达到提示性阈值（p值<5.0×10）。其中一些SNP位于先前与药物性血管性水肿相关的基因和附近，也靠近与ACEI咳嗽相关的基因，在基因水平上提供了重复，但有新的主要SNP。
我们的结果突出了非洲人群在复制研究中检测新变异的重要性。需要在整个非洲大陆进一步增加样本量并开展匹配的功能研究，以证实基因变异在理解AE-ACEI生物学机制中的重要性。
